The long-term goal of this project is to develop and optimize NIR breast tomography with the objective of identifying the most promising technical approaches which should progress into human studies designed to generate statistically-valid evidence of clinical potential. The scientific hypothesis is that optical signals in the NIR offer unparalleled opportunity to assess the molecular signatures in breast tissue available through both endogenous and exogenous contrast provided the technical challenges associated with tomographic imaging can be overcome. Clinical results obtained to date indicate that (1) NIR optical tomography when unaided by other imaging information is not likely to achieve the performance required to improve clinical decision-making in either a screening or diagnostic setting for small breast abnormalities (<1 cm), and (2) NIR optical tomography when guided by MR has significantly improved quantitative accuracy and spatial resolution which appear to make it amendable to optical characterization of breast lesions of less than 1 cm in size. These findings have motivated our proposal to continue to pursue MR-guided (MRg) NIR optical breast tomography because of the convincing evidence we have generated to date that MR guidance provides for the most accurate, spatially-resolved images of the tissue molecular characteristics that can be probed with NIR optical signals. The opportunity exists to explore potential imaging enhancements made available through exogenous agents in the MRg context as representing the most accurate data that can be obtained with either absorption or emission tomography. To realize the envisioned developments we have proposed (1) to customize a 3T breast imaging coil for simultaneous MR/NIR imaging in collaboration with Philips Medical that will incorporate a contact-insensitive fiber optic breast interface, (2) to advance the processing and reconstruction algorithms associated with concurrent use of MR images in the formation and display of volumetric NIR images of endogenous and exogenous chromophores, exogenous fluorophores and scattering parameters, (3) to optimize, evaluate and compare exogenous contrast MRg NIR imaging based on absorbing versus fluorescing agents through simulation and phantom studies, and (4) to extend the Aim 3 findings to human studies in the breast using GdTex in women with metastatic breast cancer and ICG in women with screen-detected breast abnormalities recommended for biopsy as proofs-of-principles in order to compare MRg NIR tomography of endogenous and exogenous chromophores with exogenous fluorophores when evaluated in combination with conventional contrast-enhanced breast MR. The contributions expected from the proposed research would lead to the imaging platforms required to compare directly exogenous and endogenous absorption contrast with exogenous fluorescence contrast under the optimal conditions of MRg in order to determine their respective sensitivity and specificity to breast pathology in future evaluative trials that would serve to define their relative merits and ultimately their potential clinical roles.